The hipocampus is a brain area known to be involved in learning and memory in both humans and animals. In addition, the activation of opioid receptors in the hippocampus can disrupt memory formation, and synchronous neural processes. Several studies to date have provided evidence that non-opioid peptides, such as cholecystokinin (CCK), can disrupt opioid-mediated processes, including analgesia. Therefore, we have begun studies to evaluate the hypothesis that the actions of CCK on opioid-mediated effects is due to a form of heterologous desensitization of the mu opioid receptor following activation of CCK-B receptors. These studies are conducted in the rodent brain slice preparation using whole-cell electrophysiological techniques. Studies completed to date indicate that activation of mu opioid or CCK-B receptors on hippocampal GABAergic interneurons demonstrate opposite effects on membrane potential and cellular excitability, such that CCK-B receptors excite, and mu opioid inhibit interneuron activity. Studies completed in the last period were designed to examine whether cannabinoids, as well as opioids, will interact with CCK receptors. We have expanded this study to include cannabinoids because it has become increasingly clear that the cannabinoid type 1 receptor (CB1) is located almost exclusively on CCK-containing interneurons in the hippocampus. Therefore, our first study examined the actions of cannabinoid receptor agonists on these CCK containing interneurons. This work was published in the European Journal of Neuroscience. In the next year, we will examine more directly, interactions between CB1 receptors and CCK, as well as continue our studies of CCK/opioid interactions in the hippocampus. In addition to these studies performed in brain slices, we are also utilizing the Xenopus oocyte expression system in order to assess possible direct interactions between the CCK-B receptor and either CB1 or opiate receptors. We have recently obtained the CCK-B receptor and the TASK potassium channel mRNA in order to verify the coupling of this G-protein coupled receptor to its effector, expressed in oocytes. Once the appropriate conditions for CCK-B receptor/TASK channel expression have been met, we intend to co-express CB1 and/or mu-opioid receptors in the oocytes, in order to assess possible functional interactions between these different classes of receptors. Such interactions might then lead to testable hypotheses regarding these interactions within brain slices, and would then be verified using intracellular recording techniques in this preparation.